RARE Daily

How Inhaled mRNA May Help Rare Disease Patients Breathe Easier

January 25, 2024

Primary ciliary dyskinesia is a rare, genetic disease that arises from structural defects or the absence of the cilia lining of respiratory tract. This leads to mucus littered with trapped microbes, dust, and other debris getting caught in the airways, which can lead to permanent lung damage. Ethris is developing an inhaled mRNA therapy to get the body to produce a needed structural protein to restore normal cilia structure and function. We spoke to Thomas Langenickel, chief medical officer of Ethris, about how the company’s technology overcomes existing challenges for the therapeutic use of mRNA, its ability to deliver treatments directly to the lung, and its pipeline of therapies in development.

Daniel Levine: Thomas, thanks for joining us.

Thomas Langenickel: Thanks for having me, Danny.

Daniel Levine: We’re going to talk about mRNA, Ethris, and its efforts to develop new mRNA medicines. With the emergence of the COVID-19 mRNA vaccines, mRNA moved into the popular mind, but perhaps you can begin with the technology itself and how it can be used for both vaccines and therapeutics.

Thomas Langenickel: Yeah, certainly. Messenger RNA, or mRNA, is a single stranded RNA that is important for protein synthesis. mRNA is synthesized in the nucleus of each cell from a DNA template in a process called transcription. The mRNA is then exported from the nucleus of the cell into the cytoplasm where the mRNA serves as a template itself for protein synthesis. So in that context, the mRNA carries the information that is stored in the DNA from the nucleus of the cell to the cytoplasm where protein synthesis occurs. So, with that critical biological role in mind, we can now utilize synthetically engineered mRNA to have cells produce any protein that is encoded by the mRNA. In the case of a vaccine, this is a specific viral antigen that is presented to the immune system and results in a protective antiviral immune response. But we can also use mRNA to have cells replace any missing or dysfunctional protein or produce any other therapeutic protein ranging from proteins that are released from the transfected cells to exert their biological effect all the way to structural intracellular proteins. So while the field made significant progress through the development of COVID-19 mRNA vaccines, I believe there is even a larger potential for the development of novel mRNA-based therapeutics targeting conditions with high unmet medical need.

Daniel Levine: What are the challenges of developing and delivering mRNA therapies today?

Thomas Langenickel: Well, from my perspective, there are two major limitations with current mRNA medicines, which are stability and undesired biodistribution. So let me explain these two. Current mRNA medicines require ultra-cold storage and distribution, which results in challenges during manufacturing, distribution, and handling of the drug product. According to the WHO, approximately 50 percent of vaccines, mRNA and other modalities taken together, are wasted every year, partially due to short shelf life and instability. And you can imagine that this translates to a substantial multi-billion dollar annual loss from vaccines exposed to inappropriate temperatures. In addition, currently available LNPs tend to aggregate, fuse, or show leakage of mRNA following mechanical manipulation as simple as shaking the vial or flipping the syringe. And this is a largely under-recognized problem and also presents significant challenges during manufacturing, but also during distribution and during handling by healthcare professionals and may translate into loss of potency of the drug product. As to undesired biodistribution, we know that currently available mRNA vaccines are systemically bioavailable and up to 20 percent of the vaccine dose can be found in systemic circulation. Most of the systemically available drug product is distributing then into liver and spleen. While the available mRNA vaccines have a favorable safety/benefit profile, it is certainly highly desirable to avoid biodistribution of the drug product beyond the target tissue, in particular, for indications where systemic bioavailability of a locally administered drug product does not contribute to efficacy.

Daniel Levine: Ethris has developed a suite of platform technologies. This includes its SNIM mRNA and SNAP lipid nanoparticle. I’d like to walk through those. Let’s start with the SNIM RNA platform. How does this work?

Thomas Langenickel: Yeah. SNIM, which stands for stabilized non-immunogenic RNA, SNIM RNA, describes modifications that Ethris has invented to reduce recognition of the mRNA by the immune system, and at the same time, to increase stability and potency of the mRNA. Specifically, during the synthesis of the mRNA, we are replacing a small fraction of two of the four nucleotides contained within mRNA with modified nucleotides that can also be found in nature. This means that in contrast to available mRNA vaccines, we only partially modify the mRNA, resolving in a reduction of immune recognition that is really comparable to marketed vaccines. In addition, we are utilizing other elements such as optimized sequence elements in the so-called untranslated regions of the mRNA.

Daniel Levine: Are chemical modifications that are made to mRNA unique to the nucleotide sequence or the cell types to which it’s being delivered?

Thomas Langenickel: No, that’s actually not the case. So we found that modifications that we are using in our SNIM RNA result in a very effective drug product regardless of the drug target and regardless of the cell types that are transfected.

Daniel Levine: One of the concerns with this is that you can produce an immune response. How does this prevent that from happening?

Thomas Langenickel: Yeah. Modifications of the nucleotides, whether it’s the modification scheme that is used in currently available vaccines or our modifications scheme, result in a change of the overall pattern of the mRNA molecule such that the mRNA is no longer recognized as a foreign molecule by so-called pattern recognition receptors. These are toll-like receptors and RIG-I and these receptors typically recognize foreign mRNA. That’s their function in our body, for example, following infection with an RNA virus, and then subsequently mediate a very broad immune activation. And this can be avoided or largely minimized by the use of modified nucleotides.

Daniel Levine: You’ve got a broad pipeline that’s targeting diseases of the central nervous system, of the bone, of the heart. How able are you to deliver mRNA to different tissues and cells throughout the body?

Thomas Langenickel: Yeah, so we are able to target organs of interest with our technologies, with our SNIM and SNAP technology, actually without further modification, yeah, regardless of the tissue we are targeting. And the reason for that is largely related to the fact that we can deliver through multiple routes of administration. For example, in heart disease, we can deliver directly into the heart through catheter based injection into the coronary arteries or the heart tissue itself. Our programs targeting neurological disorders rely on mRNA-based reprogramming of stem cells ex vivo. For bone programs, we have been able to develop a collagen matrix that is loaded with our LNP formulated mRNA drug product, and that can be placed into critical bone defect to stimulate bone healing for the treatment of tendon rupture, for example. We again rely on direct injection of our LNP formulated mRNA. So this shows you that our LNP platform is actually very versatile and can be utilized across therapeutic areas.

Daniel Levine: Ethris is pursuing a dual strategy of sorts with regards to its pipeline. It’s developing programs in rare diseases that are wholly owned and looking to partner for indications that are more common. Can you talk a little about your approach to this?

Thomas Langenickel: Yes. As far as our partnering strategy goes, we plan to wholly own the rare lung disease pipeline, which includes primary ciliary dyskinesia and pulmonary alveolar proteinosis, through product development, marketing authorization, and sales. And this is an area where we have done the work to build a footprint within the rare disease patient communities and the KOL networks to support the development and launch of these programs. Beyond the footprint we are building in rare lung disease, our technology enables other partners for new drug development to advance therapies for larger indications such as our ETH47 program. You mentioned we are pursuing strategic partnerships with global partners that have already a big footprint to commercialize. We do see a big niche and the potential for our technology to improve RNA-based therapeutics and vaccines in several indications through partnerships, and one example is our collaboration [that] we recently announced with Heqet where we are utilizing our SNAP LNP platform to administer non-coding RNAs for heart tissue regeneration. This application of our technology really highlights its extensive applications.

Daniel Levine: Your technology, as you alluded to, you can deliver this through inhalation. Your lead indications in rare disease are inhaled therapies. How does it work delivering mRNA through the lungs?

Thomas Langenickel: Yeah, that’s a good question. Inhaled delivery of LNP formulated mRNA is technically very challenging. And I mentioned earlier that substantial stability of the formulation is required to enable inhaled drug administration. During nebulization of liquid formulations that we would use them to administer mRNA drugs, the formulation is typically exposed to substantial sheer stress and high temperatures. This results in substantial particle aggregation with formation of LNP clusters that are more than tenfold, larger than single LNPs when using commercially available formulations. And this in turn results in devices getting clogged very rapidly. It may also impact potency of the drug product. With our SNAP LNP platform and the formulation that we have at hand, we have solved this problem. Our LNP formulation does not aggregate and is rapidly nebulizable without loss in potency. And in addition, characterization of the droplet sizes following generation of an aerosol showed that the droplet size distribution that we are getting supports distribution in the airways that is desired for our drug candidates, ETH47 and ETH42.

Daniel Levine: Your lead indication within the rare disease space is for primary ciliary dyskinesia or PCD. For people not familiar with this, can you explain what it is?

Thomas Langenickel: Yeah. Primary ciliary dyskinesia, or PCD, is a rare genetically heterogeneous disorders and primarily characterized by cilia abnormalities and respiratory disease. In the United States, we estimate that approximately 80,000 to 100,000 people are affected by PCD. To date, disease-causing mutations have been identified in over 50 genes, which encode proteins that are important for the formation and function of motile cilia and respiratory epithelial cells. These genetic mutations result in dysfunction of motile respiratory cilia, and as a result, clearance from the upper as well as lower respiratory tract of mucus, cell debris, and foreign material that we constantly inhale is severely impaired.

Daniel Levine: And how does the condition manifest itself and progress?

Thomas Langenickel: So PCD may manifest itself already in children shortly after birth who may suffer from neonatal respiratory distress that requires administration of oxygen. Upper respiratory symptoms typically include constantly running or stuffed nose and frequent or chronic infections of paranasal sinuses and the middle ear that may result in hearing impairment. Then later in life, lower respiratory symptoms include chronic productive cough, shortness of breath, frequent lung infections, sometimes with pathogens such as pseudomonas auruginosa that is very difficult to eradicate with antibiotic treatment. Chronic airway inflammation that we see in the patients and frequent lung infections often result also in structural lung damages such as bronchiectasis and a reduction in lung function.

Daniel Levine: What treatment options exist today for the condition and what’s the prognosis for someone who’s diagnosed with it?

Thomas Langenickel: So, there are currently no approved treatments for PCD available and patients typically receive symptomatic treatment to reduce mucus burden in the upper and lower respiratory tract, such as mucolytics that are administered through inhalation, and also physiotherapy. And acute and chronic infections are typically treated with antibiotics, either short term or longer term. Late stage disease may even result in structural lung damage and reduced lung function at a severity that requires lung transplantation.

Daniel Levine: What is ETH42 and how does it work?

Thomas Langenickel: So, ETH 42 is a drug candidate for inhaled administration based on Ethris’s platform technology in which the mRNA encodes protein called CCDC40. CCDC40 is a structural ciliary protein and not present in people with PCD based on mutations in the CCDC40 gene. And we are using our platform to replace the missing protein in respiratory epithelial cells with a goal to restore celia structure and function in people with CCDC40 mutations. We have selected CCDC40 as our first PCD target because mutations in this particular gene are typically associated with a high burden of disease, and so far we have been able to demonstrate in preclinical models of cilia dysfunction that ETH42 is able to really restore cilia structure and cilia function.

Daniel Levine: You have two other experimental therapies in development for the indication. Are these for different mutations or are you looking for the best of the three?

Thomas Langenickel: No, these are indeed for different mutations. So ETH43 and 44 encode different ciliary proteins than ETH42 and therefore target a very different PCD subpopulation. And as I mentioned earlier, we know of 50 genes that are associated with PCD. The versatility of our mRNA platform allows us to address many of these gene mutations by simply replacing the mRNA within the drug product. And this is exactly what we are doing with ETH43 and 44. So, we intend to move these programs forward following initial confirmation of safety and target engagement with 42.

Daniel Levine: And what’s the development path forward?

Thomas Langenickel: Yeah, so we are currently preparing for initiation of our first phase 1 clinical trial, which we plan to start this year. This first trial will be investigating the safety and tolerability of ETH42 in people with PCD based on CCDC40 mutations. We will also aim at collecting information on target protein production and potential improvement of ciliary function in the study participants. And if these results are supportive, then this first trial will be followed by larger phase 2 and clinical trials that then would aim at dose selection and demonstrating safety and efficacy of ETH42.

Daniel Levine: You talked a little about the partnering you’re doing earlier. I did want to touch on a collaboration you’re doing with Diosynvax and the Coalition for Epidemic Preparedness Innovations. This is an effort to develop a broadly protective coronavirus vaccine. What does each of the parties in the partnership bring to the collaboration?

Thomas Langenickel: Yeah, we are thankful for the fruitful ongoing partnership we have with Diosynvax and also the initial funding that we received from the Coalition for Epidemic Preparedness Innovations. We have made great progress on our collaboration with Diosynvaxc, including recently being published in Nature. It’s clear that the technology we bring to partnerships is quite attractive for vaccine companies. So Ethris is contributing its SNIM RNA and SNAP LNP and stabilizing formulation technologies. Furthermore, with our suite of platform technologies, we are designing and manufacturing the mRNA vaccine candidates containing Diosynvax’s broadly protective antigen payloads. Diosynvax is contributing its novel computational design-based multi-virus vaccine antigen payload technology. The fact that we at Ethris can provide really the full suite of mRNA and LNP technology as well as IP in-house not only made us an attractive partner for Diosynvax, but makes us attractive for other vaccine players interested in the mRNA space.

Daniel Levine: And given that this is intended to be a broadly protective vaccine, is the expectation that this would work against all strains of COVID-19 as it evolved?

Thomas Langenickel: Yes, this is correct. Based on the novel computational antigen design, we aim at the development of a vaccine candidate that is broadly effective against different variants of the SARS-CoV-2 virus.

Daniel Levine: The company raised $26.3 million in a series B venture round in February 2022. Have you been able to get additional financing through partnerships and how far will existing funding take you, and what’s the plan for raising additional capital?

Thomas Langenickel: Yeah, as a private company, we have been fortunate to find successful partners to build with through not only series B investment led by Laureus Capital that has been a great partner to us, but also through capital we receive from partnerships like Cipla, which is the largest third largest pharma company in India with a strong respiratory medicine franchise. So, we are now progressing meetings with new partners and investors at the upcoming J.P. Morgan conference next week so stay tuned as we will have more to talk about probably after JPM and in the coming months.

Daniel Levine: Thomas Langenickel, chief medical officer of Ethris. Thomas, thanks so much for your time today.

Thomas Langenickel: Thanks a lot, much appreciated.

This transcript has been lightly edited for clarity and readability.

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